Synthesis Of Conformational Constrained Nucleosides Via Alkyne And Azide Intramolecular 1, 3-dipolar Cycloaddition

Conformation restricted nucleosides extracted more attention of in recent years. They are a class of modified nucleosides, which refers to the nucleoside through the chain structure of the carbon-carbon atoms or oxygen atoms or carbon and nitrogen atoms connected by the nucleoside analogues. This more complex structure of modified nucleosides on conformational regulation and a certain limitation, and generally has a certain rigidity, with a variety of different interactions between the enzyme with high selectivity. Many conformation restricted nucleosides have a good anti-virus and anti-tumor activities, which was also embedded in "antisense" oligonucleotides and RNA interference such as high efficiency and low toxicity in treatment. This paper describes an application of azide and alkyne 1,3-dipolar cycloaddition in synthesis of 3′,5′-fused nucleosides and 3,5′-cyclonucleosides. The structure of target compound was characterized by LC-MS, 1H NMR, 13C NMR and X crystal diffraction, and conformation of the nucleoside studied too.The first part of the dissertation is concern on the background of our research. conformation constrained nucleosides and their research progress are introduced firstly. Secondly, azide and alkyne 1,3-dipolar cycloaddition reactions, their progress and their applications in nucleoside chemistry are disscussed. On the basis of these two part of research we put forward our ideas: 1) Synthesis 3′,5′-fused nucleosides and 3,5′-cyleonucleosides via intramolecular azide and alkyne 1,3-dipolar cycloaddition reactions; 2) Compounds containing triazole moiety exhibit profound activites; 3) The dipole moment makes triazole form hydrogen bonds with organisms , dipole interactions and accumulating effects readily; 4) Triazole with high chemical and biological stability may improve the pharmacokinetic properties of the nucleosides.The second part describes design and synthsis of two category of 3′,5′-fused nucleosides and 3,5′-cyleonucleosides. The first class is deoxy ribose nucleosides, in this part synthsis of cyclo precursors via sulfonation and nucleophilic substitution were used to introduce an azido group on the nuclesides and selectively alkynlation on the hydroxyl or 3-N of nucleosides. After 1,3-dipolar cycloaddition reactions in refluxing toluene or xylene four different 3′,5′-fused nucleosides were abtained, they are cyclo product of 3′-β-azido-5′-propargyl,3′-α- azido -5′- propargyl,3′-β- propargyl -5′- azido, 3′-α- propargyl -5′- azido thynidine. In the synthetic attamption of 3,5′-cyclothymidine we got cyclo precursor but the cycloaddition reaction did not carry out, and the cause of the result are disscussed thorogoughly. The second class is ribose nuclesides, similarly synthsis routes were adopted and all the cyclo precursors were synthesized, but cycloaddtions did not work either. Consulting the reason may be the 2′-substitiution make the conformation of the nucleosides quite different with the deoxy ones, it makes azido group and alkynyl too far to react with each other. At last the structure of target compounds were characterized thoroghly and refer to the literuture we concluded that it is 1,5-cycloaddition reactions in the synthesis. The conformation of one product was studied based on its crystal diffraction data. It is an N-type nucleoside with sugar moiety adopts an conformation between 2E and 23T .